The objective of the proposed research is a systematic analysis of host and viral gene expression after alpha-herpesvirus infection of the mammalian nervous system. The Specific Aims are (i) using gene array technology, I will compare cellular gene expression in primary cultures of sympathetic and sensory ganglionic neurons after infection by Herpes simplex virus type 1 (HSV-1) or pseudorabies virus (PRV). HSV-1 and PRV are two related alpha-herpesviruses able to invade and spread in the nervous system of the rat, a common host. These experiments will test the hypothesis that these diverse herpes viruses influence expression of a common set of cellular genes during acute infection. In addition, I will search for common response after infection of the functionally distinct neurons of sympathetic or sensory ganglia. (ii) I will analyze host and viral gene expression after infection of primary neuronal cultures by selected attenuated PRV and HSV-1 strains in an attempt to define the cellular responses involved in the mechanisms that attenuate these mutant viruses. (iii) I will analyze host and viral gene expression after direct infection of the CNS by PRV and HSV-1. The goal is to determine if discernible patterns of gene expression can be deduced from the many highly interconnected CNS cell types that are infected and infected. By comparing the results obtained from infection of pure neuronal cultures to results obtained from the complicated milieu of infected tissue, I seek to define key pathways of viral and host gene expression that characterize an acute CNS infection. Such information is essential to understand the interplay the infected neurons and uninfected supporting glial cells in limiting CNS pathology in a living animal. The information obtained in this study will be used to compare and contrast the host and viral response to infection by other herpesviruses.